This U19 research grant application responds to the Immune Mechanisms of Virus Control (IMVC) RFA, and is comprised of four projects, an Administrative Core, and a Mouse Resources Core, integrated into a Program of study aimed at defining the immune mechanisms of flavivirus control. Flaviviruses present major and emerging public health threats, and they share common mechanisms of genome replication, host immune induction, and immune evasion strategies. Our work will encompass studies with Dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). DENV, WNV, and JEV are among the most important mosquito-transmitted viruses globally. These viruses continually are emerging and can cause severe hemorrhagic (DENV) or neurological disease (WNV and JEV) in humans. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. Moreover, there are no approved vaccines against DENV or WNV infection for the billions of at-risk people, and the current JEV vaccines demonstrate limited durability. Thus, there is a great need to define the virus/host interactions of flavivirus control in order to identify therapeutic and vaccine strategies for treating or preventing infection. The studies in this U19 Program will investigate the overarching hypothesis that the outcome of flavivirus infection is determined by the balance of virus and host control of innate and adaptive immune programs. To investigate this hypothesis our Program will include studies on Project 1: Defining mechanisms of pathogen recognition and induction of innate immunity and inflammation against flavivirus infection; Project 2: Determining how innate immune responses impact entry, infection, and spread of encephalitic flaviviruses in the central nervous system; Project 3: Determining how innate immune responses program humoral immunity to flaviviruses; and Project 4: Defining the processes regulating T cell immunity against flavivirus infection. The management and research infrastructure support for the U19 Program will be coordinated though an Administrative Core and a Mouse Resources Core. Results from our studies will provide novel insights to guide vaccine and therapeutic strategies aimed at modulating flavivirus infection.